Lake Diana E, Hudis Clifford A
Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Drugs. 2004;64(17):1851-60. doi: 10.2165/00003495-200464170-00001.
High-dose chemotherapy is based on the scientific hypothesis that escalating the dose of drug will overcome drug resistance and improve outcome. Autologous bone marrow transplantation and, more recently, peripheral stem cell transplantation used as a means to restore marrow, made this a viable treatment for patients with selected tumours such as haematological malignancies. The role in breast cancer is less certain. Given the known as well as the potential toxicities, the objective of high-dose chemotherapy should be cure as opposed to palliation. However, the natural history of breast cancer can be protracted, with relapses occurring 15-20 years after treatment or within months of curative surgery. In breast cancer there is a positive correlation between recurrence-free and long-term survival. Therefore, the recurrence-free survival can be considered a surrogate endpoint in clinical trials. In patients with metastatic disease where cure is rare, at best, duration of a disease-free state may be a surrogate for overall benefit. Alternatively, time to progression may be another endpoint in the evaluation of treatment for metastatic disease. This is based on the assumption that quality of life is enhanced without progression of disease. Toxicity is the significant issue in the use of high-dose chemotherapy. The most common toxicity is myeloablation, potentially requiring prolonged hospitalisation. The only justification for these toxicities would be evidence of significant and meaningful benefit. A clinically relevant benefit with high-dose chemotherapy has not been seen in major randomised clinical trials of breast cancer in both the adjuvant and metastatic setting. In patients with advanced breast cancer, a small percentage may achieve long-term, disease-free survival, although there is no improvement in overall survival. Nonetheless, some investigators believe that high-dose chemotherapy holds promise, although currently this treatment is not recommended outside of a well designed prospective trial. These studies have provided useful information regarding cancer treatment. However, ongoing study of drug administration intervals, that is, dose-dense therapies, may lead to an approach that allows superior and less toxic treatment for breast cancer.
大剂量化疗基于这样一种科学假设，即增加药物剂量将克服耐药性并改善治疗结果。自体骨髓移植以及最近用作恢复骨髓手段的外周干细胞移植，使大剂量化疗成为某些肿瘤（如血液系统恶性肿瘤）患者可行的治疗方法。其在乳腺癌治疗中的作用尚不太明确。鉴于已知的以及潜在的毒性，大剂量化疗的目标应是治愈而非姑息治疗。然而，乳腺癌的自然病程可能很长，复发可发生在治疗后15 - 20年或根治性手术后数月内。在乳腺癌中，无复发生存期与长期生存率之间存在正相关。因此，无复发生存期可被视为临床试验中的替代终点。在转移性疾病患者中，治愈极为罕见，至多，无病状态的持续时间可作为总体获益的替代指标。或者，疾病进展时间可能是评估转移性疾病治疗的另一个终点。这是基于这样的假设，即疾病无进展时生活质量会得到提高。毒性是使用大剂量化疗时的一个重要问题。最常见的毒性是骨髓抑制，可能需要延长住院时间。这些毒性的唯一正当理由是有显著且有意义获益的证据。在辅助和转移性乳腺癌的主要随机临床试验中，尚未发现大剂量化疗有临床相关的获益。在晚期乳腺癌患者中，一小部分患者可能实现长期无病生存，尽管总体生存率并无改善。尽管如此，一些研究者认为大剂量化疗有前景，尽管目前在精心设计的前瞻性试验之外不推荐这种治疗方法。这些研究为癌症治疗提供了有用信息。然而，正在进行的关于给药间隔（即剂量密集疗法）的研究，可能会带来一种能让乳腺癌治疗更优且毒性更小的方法。
